We are investigating a new experimental approach for the treatment of malignant brain tumors which utilizes a new class of potent, targeted anticancer compounds, called immunotoxins. We have initiated a dose escalation trial of regional therapy with the immunotoxin transferrin-CRM107 (Tf-CRM107) for the treatment of recurrent malignant brain tumors. Tf-CRM107 is a conjugate of human transferrin (Tf) and and diphtheria toxin with a point mutation (CRM107). Tf-CRM107 binds to the transferrin receptor, which facilitates iron uptake and is present in higher number on tumor cells than on the normal cells of the brain, and the diphtheria toxin mutant kills these tumor cells to which the Tf-CRM107 binds. The purpose of the study is to evaluate the toxicity of Tf-CRM107 when delivered by intra- and peritumoral slow interstitial infusion in a dosage-escalation schedule, and to assess antitumor activity in these patients. Ten patients with malignant brain tumors (5 glioblastoma, 3 anaplastic astrocytoma, 2 metastatic lung carcinoma) that have failed standard therapy (surgical resection or biopsy, radiation therapy, and chemotherapy in some), with evidence of tumor progression, have been treated. For treatment, single or multiple silastic infusion catheters were stereotactically placed intratumorally and Tf-CRM107 was infused over 2-6 days using an external syringe pump (rates 0.5-6.0 mu l-min). The initial Tf-CRM107 concentration was 7x10-10M which has been increased by 1-2 log increments every 4 patients; the last patient was treated with 7x10/9M Tf-CRM107. Total dose has increased from 0.05 to 27.3 micrograms. Patients were to be treated monthly, and of 19 total treatments, 5 patients have been treated twice and 1 patient has been treated 5 times. Tf-CRM107 infusions were well tolerated with no severe drug-related neurologic or systemic toxicity identified to date. Three patients suffered transient worsening of a neurologic-deficit that resolved with steroids and/or mannitol. Two seizures (1 generalized, 1 focal) occurred during a total of 19 treatments. Two patients required increased steroid dosages after treatment due to prolonged increased peritumoral edema. The only systemic effect of treatment detected has been a mild transient elevation of the liver enzyme SGPT in 6 of 10 patients. Of the 4 patients with MRI follow-up >1 month, all showed areas of decreased gadolinium (Gd) enhancement within their tumors after treatment, consistent with necrosis. In these patients, evaluation of Gd-enhancing volume showed reduction of 1 of 4, no changes in 2 of 4, and progression in the last patient who had a bilateral glioblastoma. In 2 change in 2 of 4, and progression in the last patient who had a bilateral glioblastoma. In 2 of 2 patients with accessible lesions that were resected after a single infusion, histology revealed extensive necrosis in the tumors with residual tumor at the edge of the necrotic areas. We anticipate treating up to 20-30 patients to establish the maximum tolerated dose of Tf-CRM107 when delivered to brain tumors by direct infusion. Evaluation of long-term toxicity, antitumor efficacy, immune response and Tf receptor immunohistochemistry in these patients is ongoing. Also, we plan to study the distribution of 111In-transferrin achieved (when co-infused with Tf-CRM107) with single photon emission computed tomography (SPECT). This data would be used to optimize drug delivery.